Functional dyspepsia is not pathological or biochemical organic lesion but functional symptoms accompanied by continuous discomfort or pain in the upper abdominal area. Medically it means various symptoms associated with the continuous and repetitive discomfort or pain confined to the upper abdomen. Specifically non-ulcerative dyspepsia, one of the functional dyspepsia, includes all the symptoms of digestive system including satiety after a meal, anorexia, abdominal distention, an early sense of satiety, belching, discomfort or pain in the upper abdomen, brash, nausea, vomiting, gastric reflux, heartburn and others. Its pathophysiology is not clearly known yet (Panganamamula et al., Functional(Nonulcer) Dyspepsia, Current Treatment Options in Gastroenterology, 5, pp. 153-160, 2002).
Functional dyspepsia is diagnosed based on various dyspepsia symptoms without apparent organic lesion, so cure is not simple and most symptoms alternate between improvement and deterioration affected severely by diet and stress. These pathological mechanisms act together manifesting one or usually multiple symptoms.
Representative functional dyspepsia treatment includes prokinetic drugs such as domperidone, metoclopramide, levosulpride, mosapride, itopride and erythromycin. As brash and ulcer are the representative symptoms of functional dyspepsia, gastric acid suppressant and antacid are used for the treatment but these including H2 antagonist drugs usually have temporary efficacy (Vincenzo Stanghellini et al., Delayed Gastric Emptying in Functional Dyspepsia, Current Treatment Options in Gastroenterology, 7, 259-264, 2004).
Recently the development of new prokinetic agent is centered on serotonergic modulating drugs as serotonin (5-hydroxytrypamine, 5-HT) plays a central role in gastrointestinal peristaltic movement, and 80% of serotonin resides in gastrointestinal tract, especially 95% of which is distributed in intra bowel secretion cells in the small intestine.
Specific agonist and antagonist drugs for 5-HT related receptors are being developed and 5-HT4agonist is under development as a cure for functional dyspepsia as well as constipation because it facilitates prokinetic action with increased gastric contractive force and propulsive pressure. 5-HT3 antagonist is effective for suppressing vomiting and diminishing visceral hypersensitivity, and 5-HT1p agonist is being developed as functional dyspepsia cure for its relaxing mechanism in fundus ventriculi (Robin spiller, Serotonergic modulating drugs for functional gastrointestinal disease, J Clin Pharmacol, 54, pp. 11-20, 2002).
Specifically 5-HT3 receptor antagonist, granisetron, reduces rectum sensitivity in irritable bowel syndrome patients, and ondansetron is not effective for irritable bowel syndrome patients but reduces vomiting and gastric sensitivity caused by expansion when fat goes into duodenum in healthy people. Cilansetron improves gastrointestinal sensitivity modulation and the adaptability of digestive duct for gastric expansion, blocks the excitable 5-HT3 receptor associated with peristaltic movement, and raises jejunal fluid absorption. However tropisetron, ondansetron and most other 5-HT3 receptor antagonists improve the gastrointestinal fasting delay symptom in rats but the effect is not conclusive in other species including humans.
Cisapride is one of the prokinetic drugs used effectively for cure of functional dyspepsia, is 5-HT4 receptor agonist and 5-HT3 receptor antagonist, and is recognized as having a statistically significant effect compared to other drugs. The response rate of cisapride is 50-82%, higher than the rate of placebo which is 27-53%, and it is reported to be effective in more than 70% of the cases when administered for 4 to 8 weeks. It is also reported that cisapride has efficacy for the concomitant disease of irritable bowel syndrome and also improves the symptoms of patients who do not respond to the cure using dopamine antagonist of levosulpride and domperidone. After it was approved as a drug for gastro-esophageal reflux disease in 1993, it led the market with an annual revenue of 40 billion (world market: 1.3 billion dollars) but in July 2000 its sales was banned.
On the other hand, another serotonin receptor 5-HT1 B/D agonist, triptans, is effective at the dose used for migraine for gastrointestinal movement and sensitive gastro-intestine. Sumatriptan is reported to delay emptying the gastric contents but its effect is known to improve the upper abdominal symptoms as it improves the modulation of fundus ventriculi and lowers the gastrointestinal expansion response in the actual functional dyspepsia patients.
5-HT4 receptor agonist, whish is one of the newly used prokenetic drugs for functional dyspepsia cure, improves the symptoms without increasing the tension at the fundus ventriculi. Cisapride, one of the 5-HT4 receptor agonist, is effective to facilitate stomach emptying, and as to the duodenum or intragastric pressure wavelength (>6 cm), the threshold value of recognizing gastric expansion is increased not only in patients but also in healthy humans as well. 5-HT4 receptor agonist drugs include tegaserod and prucalopride but they are under clinical study and target disorders in the lower digestive system (Fraser R J, Postprandial antropyloroduodenal motility and gastric emptying in gastroparesis—effects of cisapride, Gut, 35(2), p. 172-8, 1994; Talley N.J., New and emerging treatments for irritable bowel syndrome and functional dyspepsia, Expert Opin Emerg Drugs, 7(1), p. 91-8, 2002).
Meanwhile, Korean mustard of Sinapis Semen is the ripe seeds of Brassica juncea Cosson of the Cruciferae family, contains Sinalbin, Sinapine and fatty oil, and is effective to discharge phlegm and stimulate skin. (The Korean Pharmacopoedia V Part 2 pp 453-454).
Corydalis Tuber is Corydalis ternata Nakai and other tuberous plants of the Papaveraceae family, contains Berberine, 1-Canadine, Protopine and 1-tetrahydrocoptisine, and has analgesic, sedative, antispasmodic, antiemetic and ACTH hyper-secretion actions. (The Korean Pharmacopoedia V Part 2 pp 664)
Pharbitidis Seed s are the seeds of Pharbitis nil Choisy of the Convolvulaceae family, contain roughly 11% of fatty oil and 2% of pharbitin which is resinous glucoside, and are known to have easy defecation, diuretic and insecticidal effects. (The Korean Pharmacopoedia V Part 2 pp 651).
Strychni Ignatii Semen is the seeds of Strychnos ignatii Bergius of the Loganiaceae family, contains Strychnine, Brucine, Vomicine, a-Colubrine, β-Colubrine and Loganine, and has CNS exciting, stomachic, antifungal, anti-inflammatory and analgesic effects. (Oriental Herb (galenicals) Standard Annotation, pp 175, The Korean Pharmacopoedia V Part 2 pp 633-634)
However these galenicals have been used as oriental medicine mixed with other various herbs, so there has been no report on its specific prokinetic mechanism of action.
With the background, to identify the prokinetic herb that have the treatment and preventive effects for functional dyspepsia and irritable bowel syndrome, the inventor performed the activation test for 5-HT3 and 5-HT5 receptors which correspond to prokinetic trigger points and identified the candidate herb activating the receptors. Based on this, appropriate herb extracts have been found through animal model experiments for functional dyspepsia.
Also, the inventor found that the herb extracts of this invention are 5-HT3 antagonist facilitating antiemetic and gastric emptying, and suppressing visceral hypersensitivity, and are 5-HT4 receptor agonist showing prokinetic and treatment effects for irritable bowel syndrome accompanied by constipation and chronic colitis. The invention was completed by confirming the fact that the herbs individually or in combination have the cure effect for functional dyspepsia and irritable bowel syndrome.